This proposal investigates the mechanisms responsible for loss of mucus-producing conjunctival goblet cells in dry eye. Dry eye is one of the most prevalent medical conditions that decreases quality of life due to irritation symptoms and visual disturbance at a great cost to society. A hallmark of aqueous tear deficiency is loss of conjunctival goblet cells. Goblet cell secretions are essential for maintaining a stable tear film. Our preliminary data indicated that goblet cells are components of the ocular mucosal immune system and that goblet cell maturation and mucus secretion is regulated by T-helper cytokines. The T-helper 2 cytokine IL-13 promotes goblet cell maturation and mucus production while the Th1 cytokine interferon gamma inhibits goblet cell maturation. Interferon gamma increases in the conjunctiva in dry eye. This grant investigates the hypothesis that interferon gamma represses conjunctival goblet cell maturation by increasing expression of FoxA2, a transcriptional repressor of MUC5AC mucin, as well as the IL-13 decoy receptor, IL-13 receptor alpha 2 that avidly binds IL-13 and inhibits IL-13 signaling in goblet cells. Three specific gains are proposed to investigate this novel hypothesis. This proposal addresses a gap in knowledge regarding the mechanism of goblet cell loss in dry eye. At the conclusion of this project, we will better understand the molecular mechanisms by which interferon gamma antagonizes the goblet cell promoting activity of IL-13. We will also determine whether IL-13 supplementation and/or interferon gamma neutralization have therapeutic potential for promoting goblet cell maturation in dry eye. The end product of this project will be a fundamental new understanding of the regulation of conjunctival secretory function by these T-helper cytokines and novel strategies to maintain goblet cell promoting environment in the conjunctiva in dry eye disease. PUBLIC HEALTH RELEVANCE: Loss of secretory goblet cells in the conjunctiva in dry eye is associated with greater irritation symptoms and ocular surface disease. We hypothesize that goblet cell maturation in dry eye is repressed by the T helper cytokine, interferon-gamma. The overall goal of this proposal is to define the mechanisms by which interferon-gamma inhibits goblet cell maturation in dry eye and discover new and novel ways to manipulate the balance of T-helper cytokines to promote goblet cell differentiation.